This project is centered on the insulin-like growth factor type 1 receptor (IGF-1R), and its ability to regulate cellular proliferation and transformation. It is based on substantial evidence that an overexpressed IGF-IR is transforming, while, on the contrary, a decreased expression or functional impairment lead to reversal of the transformed phenotype in several cell types. Furthermore, the mitogenic and transforming functions can be localized to different domains of the IGF-IR, and a number of experiments indicate that other substrates of the receptor (besides the known ones, IRS-1, IRS-2 and Shc) must be involved. The project will endeavor: 1) to search for new substrates of the IGF- IR, especially of its C-terminus, where the transforming function is localized, by the yeast two-hybrid system; 2) to analyze the biological functions of one of these new substrates, Grb10, identified through the yeast two-hybrid system. Grb10 binds to the IGR-IR but not to a receptor truncated in the C-terminus: 3) to investigate in depth a novel finding, that IGF-II stimulates mitogenesis through the insulin receptor; and 4) to explore the quantitative aspects of IGR-IR action, and its relation to PDGE stimulation. The findings of our laboratory that mitogenesis and transformation can be dissociated at a molecular level, and that several strategies targeted against the IGF-1R (antisense plasmids, dominant negatives, antibodies) inhibit transformation and tumorigenesis clearly point out the relevance of these studies to the cancer problem, both from a basic point of view and from a practical point of view.